Pheochromocytoma and myocardial infarction.

Abstract: Pheochromocytomas are rare chromaffin cell tumors, 90% of which arise from the adrenal glands. Pheochromocytomas presenting with true myocardial infarction are even more rare. We report a 76-year-old man who had a previously undiagnosed pheochromocytoma, and presented with the uncommon complication of myocardial infarction. Our high-risk patient was managed with the combination of simultaneous coronary artery bypass grafting and adrenalectomy.

Key Words: metyrosine, myocardial infarction, pheochromocytoma

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Case Report

A 76-year-old, previously healthy male had a several-year history of episodes of anxiety, which he usually overcame by avoiding stressful situations. As the owner of a diving board manufacturing company, the patient was often engaged in legal conflicts. During an intense deposition where four prosecution lawyers were questioning him, he became quite nervous. The patient said he "couldn't control [his] nerves" and developed nausea and cold sweats on the forehead. Later he noticed mild chest discomfort and right upper quadrant abdominal pain. He presented to the emergency department (ED) with these complaints.

In the ED his blood pressure was 260/130 mm Hg, and his heart rate was 140/bpm and regular. The physical examination revealed mild bilateral basilar crackles, with no jugular venous distention, and normal heart sounds. He had tenderness in the right upper quadrant of the abdomen, with voluntary guarding. No abdominal bruit was heard, and there was no peripheral pedal edema.

The laboratory values were as follows: urinalysis showed hematuria (4+) and proteinuria (albumin 3+). White blood cell count was 17.8 X 1000 cells/[min.sup.3]; hemoglobin 16.5 g/dL; and hematocrit 52.7%. Serum electrolytes were normal and blood urea nitrogen/creatinine was 17/1.8 mg/dL, with glucose of 324 mg/dL and albumin 4.7 mg/dL. The cardiac enzymes are shown in Table 1.

The serial electrocardiograms showed initial sinus tachycardia with poor R wave progression, and later demonstrated loss of R wave anteriorly, consistent with anterior infarction. The biochemical markers used to diagnose pheochromocytoma are in Tables 2 and 3.

A computerized tomography (CT) scan of the abdomen revealed a large right retroperitoneal hemorrhage centered near a mass of approximately 8 cm that most likely represented an adrenal mass, as shown in Figure 1. There also was hemorrhage in the mass itself. The [I.sup.131] metaiodobenzylguanidine (MIBG) scan showed intense [I.sup.131] MIBG uptake inferomedial to the right hepatic lobe at the location of the right adrenal gland. The echo showed segmental wall motion abnormalities consisting of apical akinesis, mild anterior and anteroseptal hypokinesis, and ejection fraction of 45 to 50%.

The patient's cardiac catheterization showed a left main artery calcified distal 50% stenosis, and the left anterior descending artery had a high grade complex proximal stenosis of 80%. The first and second diagonal arteries proximally had approximately 80% stenoses.

The patient was diagnosed with accelerated hypertension secondary to pheochromocytoma and myocardial infarction (MI). His hypertensive episodes were initially managed with nitroprusside, and his blood pressure stabilized at 140/80 mm Hg. The patient was then started on phenoxybenzamine 10 mg orally twice a day to provide an appropriate alpha blockade, so as to minimize the effects of hormonal surges, which can lead to spontaneous retroperitoneal hemorrhage. His systolic blood pressure subsequently dropped to the range of 90 to 100 mm Hg and therefore did not allow him to tolerate the maximum dose of phenoxybenzamine. The dose was reduced and he was started on a low dose of metyrosine as a part of his preoperative treatment, the dosage of which was gradually increased to 4 g per day with no side effects.

Due to the hemorrhage in the mass and retroperitoneum, aspirin and heparin were not given for his MI. The patient was started on carvedilol 3.125 mg orally twice a day, because of the combined alpha and beta blockade effects. After stabilization, the patient was taken for cardiac catheterization, which revealed the above-stated findings. The patient tolerated the medications well without any side effects and remained normotensive and hemodynamically stable. The patient was well hydrated during the hospital course.

After 10 days of phenoxybenzamine and metyrosine, the patient was taken for combined coronary artery bypass grafting (CABG) and adrenalectomy. There was one episode of increased blood pressure to 200/140 mm Hg during the tumor manipulation, which was well controlled with nitroprusside. The patient had an uneventful postoperative course, and remains well. Gross examination of the tumor showed 300 g of enlarged necrotic and hemorrhagic adrenal gland tumor. The entire specimen was 14 X 10 X 6 cm. The circumscribed round tumor was approximately 8 cm in diameter.

On follow-up, the biochemical markers for pheochromocytoma were normalized and are shown below in Table 4.

Discussion

Pheochromocytomas can cause hypertension, glucose intolerance, dyslipidemia, and enhanced coagulation. (1) Catecholamines can also cause irreversible damage to the intima and vasa vasorum, and increased levels can compromise myocardial oxygen supply and demand, thus predisposing one to coronary artery disease (1) and MI.

[FIGURE 1 OMITTED]

Diagnosis

When there is a high suspicion and a periodic hormone secreting spell, 24-hour urinary metanephrines (2) and catecholamines are a good test, as shown in Table 2. In between the spells, fractionated free plasma metanephrines may still be elevated despite normalization of other biochemical markers, as made evident in Table 3. Therefore some authors feel that 24-hour urinary metanephrines and catecholamines be abandoned for the less specific fractionated free plasma metanephrines for screening of pheochromocytomas in all settings. (3) Once biochemically proven, localization by abdominal CT scan/magnetic resonance imaging should be attempted, and if they are negative, an [I.sup.131] MIBG scan can be helpful.

Treatment

Preoperative medical blockade. Catecholamine release related to induction of anesthesia or tumor manipulation often leads to severe hypertension, arrhythmias, or stroke. Medical blockade (Table 5) of tumor catecholamine is associated with significant decrease in mortality.

Metyrosine, a tyrosine hydroxylase inhibitor, blocks the conversion of tyrosine to dopa and is a possible addition to preoperative medical blockade. It decreases catecholamine production by 50 to 80%. Combined use of alpha blockers and metyrosine therefore results in improved hemodynamic control, less blood loss, and less need for the intraoperative use of vasopressors and phentolamine, as evident in Figure 2. (4) In this case, the patient did not tolerate an adequate dose of phenoxybenzamine due to hypotension, and metyrosine was added to provide better preoperative blockade. The patient did well during surgery, and there was only one brief episode of hypertension during the tumor manipulation, which was managed effectively.

Surgical management. After appropriate proposed medical management, the next step was to surgically manage the patient with CABG and adrenalectomy. There have been case reports of severe coronary artery disease and pheochromocytoma, without recent MI, managed with CABG and adrenalectomy a few weeks apart. Although there are no controlled studies indicating a preferred approach, the literature revealed four case reports where both procedures were managed together. (2,5-11) We were uncomfortable sending our patient to adrenalectomy first because the removal could lead to a hormonal surge during tumor manipulation and, consequently, possible fatal MI. We were also hesitant to perform CABG first, as the large hemorrhagic, necrotic tumor might be predisposed to another hemorrhagic bleed leading to another pheochromocytoma crisis and causing more complications.

We opted to combine both procedures in one setting due to the patient's high-risk status. The advantages were a one-time induction of anesthesia and an improved ability to manage intraoperative complications. We took this approach and did CABG first, leaving the sternotomy open during the adrenalectomy that followed so any bleeding in the chest ensuing from a hypertensive episode could be rapidly identified and controlled. Adrenalectomy followed CABG, and no unusual bleeding occurred, despite the brief period of hypertension during the adrenalectomy. Both incisions were closed at the conclusion of the procedure.

Conclusion

In summary, with appropriate preoperative medical blockade of phenoxybenzamine and metyrosine, combined CABG and adrenalectomy were done, respectively, in one setting without any major complications. The patient has done well postoperatively.

The true measure of a man is how he treats someone who can do him
absolutely no good.
--Samuel Johnson

Table 1. Serial cardiac enzyme values

                                     Time
                       Normal    0       8     12
Cardiac enzymes        values   hour    hour  hour

Creatine kinase (U/L)  21-215   282     538   390
MB fraction (ng/mL)     0-4      35      50    14
MB index (% index)      0-6      12%      9%    4%
Troponin I (ng/mL)      0-0.04    6.24   NA      .62

Table 2. 24-hour urinary catecholamines and their metabolites at
presentation (a)

                                       Values during  Normal
Biochemical markers                        crisis     values

Urinary dopamine (pg/mL)                   203         0-20
Urinary epinephrine (pg/mL)                558        10-200
Urinary nonepinephrine (pg/mL)         103,360        80-520
Urinary VMA (mg/d)                          19.1       0-7
Urinary metanephrines ([micro]g/d)         295        30-350
Urinary normetanephrines ([micro]g/d)     7100        50-650

(a) VMA, vanillymandelic acid.

Table 3. 24-hour plasma and urinary catecholamines and their metabolites
after the crisis

                                       Values after  Normal
Biochemical markers                     the crisis   values

Urinary dopamine (pg/mL)                 39           0-20
Urinary epinephrine (pg/mL)              33          10-200
Urinary nonepinephrine (pg/mL)         2291          80-520
Plasma free normetanephrines (nmol/L)    12.1        <0.90
Plasma free metanephrines (nmol/L)        0.31       <0.50

Table 4. 24-hour urinary catecholamines and their metabolites on
follow-up

                                       Values on  Normal
Biochemical markers                    follow-up  values

Urinary dopamine ([micro]g/d)             308     60-440
Urinary norepinephrine ([micro]g/d)        65      0-100
Urinary metanephrines ([micro]g/d)        103     30-350
Urinary normetanephrines ([micro]g/d)     482     50-650

Table 5. Preoperative medical blockade of pheochromocytoma (10 to 14
days before surgery)

Alpha blocker phenoxybenzamine
  10 mg orally two times a day and increase the dose gradually with
    careful monitoring of supine and upright blood pressures
  Usual range: 20-40 mg, 2-3 times a day
  Major side effects: postural hypotension, tachycardia, and syncope

Beta-adrenergic blockers
  Given to patients with tachycardia only after adequate alpha blockade
  Administration of propranolol before alpha blockade can worsen
    hypertension secondary to unopposed vasoconstriction
  Propranolol 10 mg 3-4 times per day; can be a starting dose and
    increased as needed to control heart rate

Metyrosine
  250 mg every 6 hours
  Increase dose to 250-500 mg/d to control blood pressure or symptoms
    (maximal dose 4 g/d)
  Major side effects: drowsiness, extrapyramidal symptoms, and diarrhea

Adequate hydration and liberal salt intake to restore the contracted
   plasma volume to normal

Night before surgery: at 12 am phenoxybenzamine at 1 mg/kg and
   metyrosine at 1 g

Patients Not Requiring Pressors or Phentolamine During Surgery, %

                                             Pressors  Phentolamine

Metyrosine and Phenoxybenzamine or Prazosin    95%         81%
Phenoxybenzamine Alone                         50%         33%
No Medication (None)                           40%         29%

Fig. 2 Distribution of patients not requiring pressors or phentolamine
during surgery according to preoperative treatment (100%). Total number
of patients per group (n = 21, metyrosine; n = 6, phenoxybenzamine; n =
5, none). Two patients who died (none group) are not included in this
figure (pressors, none bar). Adapted with permission from Archives of
Internal Medicine 1997;157:905. Copyrighted 1997, American Medical
Association.

Note: Table made from bar graph.

Acknowledgments

The authors would like to offer a special thanks to Dr. Bruce Lowe, Dr. Mark Metzdorff, and Dr. James Neifing for helping us to manage this difficult case, and for assistance with this article. Thanks are also extended to Dr. Elizabeth Eckstrom, Dr. Stephen Jones, and Ekta R. Garg for editorial assistance.

Accepted July 11, 2004.

References

1. Baillargeon JP, Pek B, Teijeira J, et al. Combined surgery for coronary artery disease and pheochromocytoma. Can J Anaesth 2000;47:647-652.

2. Lenders JW, Pacak K, Walther MM, et al. Biochemical diagnosis of pheochromocytoma: which test is best? J Am Med Assoc 2002;287:1427-1424.

3. Kudva YC, Sawka AM, Young WF. The laboratory diagnosis of adrenal pheochromocytoma: the Mayo Clinic experience. J Clin Endocrinol Metab 2003;88:4533-4539.

4. Steinsapir J, Carr AA, Prisant LM, et al. Metyrosine and pheochromocytoma. Arch Intern Med 1997;157:901-906.

5. Nielson DH, Tomasello DN, Brennan EJ, et al. Concomitant coronary artery bypass grafting and adrenalectomy for pheochromocytoma. J Cardiac Surg 1995;10:179-183.

6. Seah PW, Costa R, and Wolfenden H. Combined coronary artery bypass grafting and excision of adrenal pheochromocytoma. J Thorac Cardiovasc Surg 1995;110:559-560.

7. Balabaud-Pichon V, Bopp P, Levy F, et al. Excision of adrenal pheochromocytoma and coronary artery bypass graft surgery with cardiopulmonary bypass. J Cardiothoracic Vascular Anesth 2002;16:344-346.

8. Walther MM, Keiser HR, and Linehan WM. Pheochromocytoma: evaluation, diagnosis, and treatment. World J Urology 1999;17:35-39.

9. Eisenhofer G, Huynh T, Hiroi M, et al. Understanding catecholamine metabolism as a guide to the biochemical diagnosis of pheochromocytoma. Rev Endocrine & Metabol Disord 2001;2:297-311.

10. Manger W, Gifford R. Pheochromocytoma. J Clin Hypertens 2002;4:62-72.

11. Sawka AM, Jaeschke R, Singh RJ, et al. A comparison of biochemical tests for pheochromocytoma: measurement of fractionated plasma metanephrines compared with the combination of 24-hour urinary metanephrines and catecholamines. J Clin Endocrinol Metab 2003;88:553-558.

RELATED ARTICLE: Key Points

* The best biochemical marker to diagnose pheochro-mocytoma is plasma free metanephrine.

* Metyrosine decreases catecholamine production by 50 to 80%, and can be used with alpha-blocking agents to decrease intraoperative complications due to hormonal surges.

* Adrenalectomy combined with coronary artery bypass graft may be considered a good option for managing pheochromocytoma and coronary artery disease together.

Anuj Garg, MBBS, MD, and Peter F. Banitt, MD

From the Legacy Emanuel and Good Samaritan Hospitals. Portland, OR.

Reprint requests to Anuj Garg, MD, Legacy Clinic, Good Samaritan, 1200 NW 23rd Avenue, Portland, OR 97210. Email: [e-mail]